The long-term objectives of this research program are to determine the behavioral. physiological and biochemical associations of aberrant alcohol-seeking behavior and to elucidate underlying mechanisms. To this end, we have developed the alcohol-preferring P and alcohol-nonpreferring NP lines of rats through selective breeding and have shown that the P line satisfies all the perceived requirements of an animal mode) of alcoholism. The P and NP rats are now in the 27th generation of selection. We are also performing duplicate bidirectional selection or high-alcohol- drinking (HAD-1 and HAD-2) and low-alcohol-drinking (LAD-1 and LAD- 2) lines from the N/Nih heterogenous stock rats. These lines have now reached the S-7 generations. The objectives of this new selection experiment are to address the issue of generality of a number of discovered associations of high alcohol-seeking behavior and to establish the HAD line as another suitable animal model of alcoholism. We propose to continue the maintenance of the P and NP lines and to continue the selective breeding of the HAD and LAD lines. These animals will be used to test the general hypothesis that an enhanced responsiveness to the low-dose reinforcing effects of alcohol and the rapid development and persistence of tolerance to the high-dose aversive effects of ethanol promote high alcohol- seeking. behavior. To this end, the association of these traits in F2 offspring of P and NP crosses will be studied, and backcrosses to the parent P and NP lines will.be made. A major effort in the next 5 years will be the elucidation of the underlying neurobiological basis of the differences in these behavioral responses. Place preference and intracranial self- stimulation experiments will be performed to further examine the reinforcing properties of ethanol. The CNS sites responsive to the low-dose rewarding properties of ethanol and participating in tolerance development will be localized by selective lesioning, by single unit electrophysiological recording and by site-specific administration of ethanol. Neurotransmitter/neuroregulator systems to be studied include serotonin, dopamine. gamma-aminobutyric acid, vasopressin and opioid peptides. Differential responses of these systems to alcohol between P and NP rats and between tolerant and nontolerant animals will be assessed by measurements of in vivo release, neuronal activity and receptor function. A newly discovered association of alcohol preference, heterozygosity at four genetic marker loci, will be studied in relation to dominance or overdominance of the plus alleles for alcohol preference.